TB is a global health emergency of mammoth proportions, annually causing the death of almost two million people. A quarter of a century after the discovery of its causative agent, AIDS continues to wreak havoc on a global scale, having caused 25 million deaths. The combined toll of AIDS and TB is devastating. About 11 million people are yearly co- infected with HIV and Mtb. Both diseases potentiate the pathogenesis of the other. New and efficient vaccines and drugs are urgently needed to control these pandemics. It is therefore necessary to understand the molecular mechanisms of TB and AIDS infections and TB/AIDS co-infection, while using appropriate animal models. Nonhuman primates have long been recognized as excellent models of AIDS. Recent work has shown that nonhuman primates are also excellent models of TB. These animals generate various disease outcomes depending upon dose of infection and display a complete range of human pulmonary tuberculous granulomatous lesions. We have established a nonhuman primate model of TB/AIDS co-infection via natural routes of infection. The immune system responds to Mtb infection by inducing granulomatous pulmonary pathology. This response is coordinated by CD4+ T lymphocytes, which are selectively depleted in mucosal immune sites including the lung during AIDS (a.k.a SIV infection of nonhuman primates). The regulation of granulomatous response is a key event, since its dysregulation can result in over-exuberant inflammation and tissue damage (immunopathology). Regulators of the granulomatous immune response include FoxP3+ regulatory T cells, IL10 and IL27. Mediators of the granulomatous immune response immune response include TNFa, IFNg, and the JNK/STAT signaling pathways. The discovery of miRNAs is a major recent breakthrough in biology. miRNAs are small RNA molecules that act as regulators of gene-expression via sequence complementarity. miRNAs play a role in managing tissue inflammation resulting from immune response. In fact, many of the mediators and regulators of the granulomatous immune response listed above have been shown to be targets of miRNA mediated regulation. Our preliminary data shows that the granulomatous immune response to aerosolized Mtb infection in nonhuman primates is accompanied by the changes in the global miRNA profile, including the induction of miR-223 and miR-21 - which play roles in suppression of premature neutrophil activation, polarization of the Th immune response. Similarly miR-155, involved in the initiation of potent innate immune responses is repressed in NHP TB granulomas. We hypothesize that changes in miRNA expression profile response to Mtb infection are intended to regulate the granulomatous immune response and minimize immunopathology. We therefore propose to study miRNA expression profiles in the lungs of nonhuman primates exposed to low and high doses of Mtb. To further dissect the role of individual miRNAs expressed in CD4+ lymphocytes, we also propose to study miRNA expression profiles in the lungs of nonhuman primates exposed to low and high doses of Mtb and co-infected with SIV. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) and Acquired Immune Deficiency Syndrome (AIDS) are global health emergencies of mammoth proportions, annually causing the death of almost four million people. We have established a nonhuman primate model of TB/AIDS co-infection via natural routes of infection. miRNAs are small RNA molecules that act as regulators of gene- expression via sequence complementarity. miRNAs play a role in managing tissue inflammation resulting from immune response. We hypothesize that miRNAs silence the extremely high levels of pro-inflammatory molecules initially present in primate granulomas following Mtb infection. We propose to study the miRNA profile in response to TB infection and TB/AIDS co-infection in nonhuman primates.